Neuroepidemiology of Parkinson’s disease in an urban area of Iran : from screening and prevalence to nutritional, clinical and psychiatric features and quality of life

Background. Parkinson’s disease (PD) is the second most common neurodegenerative disorder with complex presentations consisting of different motor and non-motor symptoms. The multisystem and progressive nature of PD has made it a complicated entity with broad variation in manifestations and reciprocal effects on several aspects of daily life. Aims. This doctoral thesis investigated different neuroepidemiologic aspects of PD and parkinsonism including its screening and prevalence in the urban area of Tehran, Iran, nutritional status and risk factors for malnutrition, clinical and psychiatric features, healthrelated quality of life (HRQoL) and its determinants in Iranian PD patients. For this purpose, we also aimed to validate several questionnaires and make a new screening instrument. Study I. Psychometric properties of the Persian-translated version of the short-form Parkinson’s disease questionnaire (PDQ-8) were assessed in 114 Iranian patients with PD consecutively recruited from an outpatient Movement Disorder Clinic. The Cronbach’s alpha coefficient of the entire PDQ-8 was 0.740 (95% CI: 0.661-0.806). Replacement of PDQ-8 items with other questions with the highest internal consistency within each dimension of the long-form PDQ (PDQ-39) did not further improve reliability. The Persian version of the PDQ-8 was shown to be a valid and reliable instrument to assess HRQoL in Iranian PD population especially in mental and behavioral aspects. PDQ-8 is a practical and informative instrument in daily clinical practice where clinicians are in shortage of time and need a validated self-reported brief questionnaire. Study II. To develop a new instrument for screening of parkinsonism in community-based surveys, a comprehensive questionnaire consisting of 25 items on different PD symptoms was filled in 157 patients with parkinsonism and 110 controls. Using the concept of clinical utility index (CUI), six items on “stiffness & rigidity”, “tremor & shaking”, “troublesome buttoning”, “troublesome arm swing”, “feet stuck to floor” and “slower daily activity” demonstrated good validity (CUI≥0.64) to be included in the new screening tool . We introduced a new set of six items to screen parkinsonism, which showed higher diagnostic values [area under curve (AUC)=0.977] compared to the previously developed questionnaires. This new instrument could be used in population-based surveys to screen parkinsonism in poor-resource settings. Study III. Following a random multistage sampling of the households within the network of “Health Centers” with 374 subunits in all 22 urban districts of Tehran, 20,621 individuals answered the baseline checklist and the screening questionnaire developed in study II. Data from 19,500 persons aged ≥30 years were entered in the final analysis. A total number of 157 cases were positively screened for parkinsonism that resulted in age- and sex-adjustment prevalence rates of 222.9/100,000 (95% CI: 160-300) and 285/100,000 (95% CI: 240-329) based on the real Tehran population and “WHO World Standard Population”, respectively. The male/female ratio of probable parkinsonism was 1.62 and there was a steady increase by advancing age. The calculated rates for the prevalence of parkinsonism in our study are closer to the reports from some European and Middle-East countries, higher than reports from the Eastern Asian and African populations, and lower than Australia. The prevalence rate of >200/100,000 for parkinsonism in Tehran, Iran is considered as a medium-to-high rate. Study IV. Nutritional status was evaluated in 143 Iranian PD patients and 145 age- and sexmatched controls by means of the validated Persian version of the mini-nutritional assessment (MNA). The mean of total MNA score was not significantly different between the two groups [24.4 (SD=3.8) in controls vs. 25.1 (SD=3.4) in PD patients, p=0.094]. Three (2.1%) PD patients were suffering from malnutrition and another 37 (25.9%) were at risk of malnutrition; while in control group similar feature was observed (2.0% malnourished and 35.2% at risk of malnutrition, p=0.228). Our findings indicated similar nutritional status among mild-to-moderate PD patients and matched controls from the same community. However, nearly one third of PD population were either malnourished or at risk of malnutrition necessitating more attention towards nutritional assessment in PD. Study V. Factors affecting nutritional status were investigated in 150 PD patients including a comprehensive list of motor and non-motor scales. The total score of the Unified Parkinson's disease rating scale (UPDRS) scale (r=-0.613, p<0.001) and PD duration (r=-0.284, p=0.002) had a significant inverse correlation with the total MNA score. A higher Hoehn and Yahr stage [2.5 vs. 2.0, p<0.001], more severe anxiety [8.8 vs. 5.9, p=0.002], depression [9.0 vs. 3.6, p<0.001] and fatigue [5.4 vs. 4.2, p<0.001] were observed in PD patients with nutritional insufficiency. Except for stigma, all other domains of the HRQoL significantly correlated with the total MNA score. We showed that disease duration, severity of motor and psychiatric symptoms (depression, anxiety) and fatigue associated with nutritional status in PD, which itself affected different aspects of HRQoL especially the emotional well-being and mobility. Study VI. A broad spectrum of demographic, motor and non-motor characteristics were evaluated in 157 PD patients consisting of comorbidity profile, nutritional status, UPDRS (total items), psychiatric symptoms (depression, anxiety), fatigue and psychosocial functioning through physical examination, validated questionnaires and scales. Structural equation model (SEM) and multivariate regressions were applied to find determinants of Parkinson’s disease severity index (PDSI) and different domains of HRQoL (PDQ-39). Female sex, anxiety, depression and UPDRS-part II scores were the significant independent determinants of PDSI. A structural model consisting of global motor, global non-motor and co-morbidity indicator as three main components was able to predict 89% of the variance in HRQoL. However, outstanding heterogeneities in the pattern and determinants of HRQoL were found among different PD phenotypes. Conclusions. We showed a medium-to-high prevalence rate for suspicious parkinsonism in Iranian population living in the urban area of Tehran by means of a novel 6-item screening instrument. Similar nutritional status was found in mild-to-moderate PD patients and matched controls from the same community. Yet, approximately one third of people with mild-tomoderate PD were either malnourished or at risk of malnutrition. Duration of PD, severity of motor symptoms, depression, anxiety and fatigue associated with nutritional status in PD patients. Motor symptoms affecting activities of daily living (ADL), depression, anxiety and female sex were found to be the strongest independent determinants of HRQoL in Iranian PD population. Clear heterogeneities were found in the pattern and determinants of HRQoL in different PD phenotypes, which should be considered during the assessments and developing personalized interventions to improve life quality in PD patients with different prominent features

PhD Education Challenges - Doctoral Candidates’ Perspectives

Doctoral training was included in the Bologna system as the third cycle. The important consequence of this change is that the doctoral studies became more structured, and most universities now train doctors in a shorter time period than in the past, mostly in 3 to 4 years. The National Association of PhD students from Serbia (Doktoranti Srbije) conducted the same survey in the form of a questionnaire three years in a row (2010-2012). In 2010 the survey received 335 responses, in 2011 there were 557 responses and in 2012 there were 625. The survey results showed that doctoral candidates recognise supervision as a key issue that need to be improved. Surveyed individuals emphasised the impact of the supervisor’s engagement on the quality of their PhD projects. Supportiveness is the quality that PhD students value the most. This involves supervisors being encouraging, and aware that students' lives extend beyond the PhD. Other key areas for improvement, according to Serbian PhD candidates, are financing and mobility, especially international mobility

Evolution of Orofacial Symptoms and Disease Progression in Idiopathic Parkinson’s Disease: Longitudinal Data from the Jönköping Parkinson Registry

Background. Orofacial symptoms are common in Parkinson’s disease (PD) both as initial manifestations and late markers of disease complications. We aimed to investigate the evolution of orofacial manifestations and their prognostic value throughout PD progression. Methods. Data was obtained from “Jönköping Parkinson Registry” database on routine care visits of 314 people with idiopathic PD in southern Sweden. Information on baseline symptomatology, orofacial features, UPDRS, and medications was recorded at baseline and during each follow-up visit within an average of 4.2 (range: 1–12) years. Results. Hypomimia, affected speech, drooling, and impaired swallowing were present in 37.3%/91.6%, 14.1%/65.5%, 11.7%/55.3%, and 10.2%/34.5% at baseline/follow-up, respectively. Male sex [OR = 2.4 (95% CI: 1.0–5.9)], UPDRS motor scores [OR = 1.2 (95% CI: 1.1–1.3)], dominant rigidity [OR = 5.2 (95% CI: 1.4–19.1)], and autonomic disturbance [OR = 3.4 (95% CI: 1.1–10.9)] were risk factors for drooling. Individuals with more severe orofacial burden at baseline had shorter median time to develop UPDRS-Part III > 28 [3rd tertile = 4.7 yr, 2nd tertile = 6.2 yr, and 1st tertile = 7.8 yr; p = 0.014]. Conclusions. Majority of people with PD manifest orofacial manifestations at either early or late stages of the disease. PD severity, symmetry of motor disturbances, and autonomic disorders correlate with orofacial symptoms. Individuals with more severe orofacial burden at baseline progressed faster to more advanced stages

Clinimetrics of the Freezing of Gait Questionnaire for Parkinson Disease During the "off" State

Introduction: Freezing of gait, a common PD motor symptom, could increase the risk of falling. This study aimed to investigate the clinimetric attributes of the Freezing of Gait Questionnaire (FOGQ) for people with Parkinson disease in the "off" state. Methods: A total of 115 patients with Parkinson disease (PD; mean age, 60.25 years) were included. Acceptability, internal consistency (by the Cronbach alpha, and test-retest by Intraclass Correlation [ICC]), and reliability of the Persian-translated version of the FOGQ were examined. Dimensionality was estimated by Exploratory Factor Analysis (EFA). Fall efficacy scale-international, unified Parkinson disease rating scale-II, Berg balance scale, functional reach test, and Parkinson disease questionnaire-39 were applied to determine the convergent validity. Diagnostic accuracy for obtaining optimal cutoff point, separating faller and non-faller groups, was analyzed by Receiver Operating Characteristics (ROC) curve analysis and Area Under the Curve (AUC). All tests were carried out in an "off" state. Results: The Cronbach alpha was high (α=0.92). The test-retest showed high reliability (ICC=0.89). The FOGQ was unidimensional according to the EFA and had acceptable convergent validity with moderate to high correlation with other clinical scales. The optimal cutoff point to discriminate fallers from non-fallers during the "off" state was 9/10, with an AUC of 0.92. Conclusion: Our results suggest that the FOGQ has appropriate reliability, validity, and discriminative ability for measuring FOG in patients with PD during the "off" state.S

Comparison of the Psychological Symptoms and Disease-Specific Quality of Life between Early- and Typical-Onset Parkinson’s Disease Patients

The impact of Parkinson’s disease (PD) on psychological status and quality of life (QoL) may vary depending on age of disease onset. The aim of this study was to compare psychological symptoms and disease-specific QoL between early onset versus the rest of the PD patients. A total number of 140 PD patients with the mean current age of 61.3 (SD=10.4) yr were recruited in this study. PD patients with the onset age of ≤50 yr were defined as “early-onset” (EOPD) group (n=45), while the ones with >50 yr at the time of diagnosis were categorized as the “typical-onset” (TOPD) patients (n=95). Different questionnaires and scales were used for between-group comparisons including PDQ39, HADS (hospital anxiety and depression scale), FSS (fatigue severity scale), MNA (mininutritional assessment), and the UPDRS. Depression score was significantly higher in EOPD group (6.3 (SD=4.5) versus 4.5 (SD=4.2), P=0.02). Among different domains of QoL, emotion score was also significantly higher in the EOPD group (32.3 (SD=21.6) versus 24.4 (SD=22.7), P=0.05). Our findings showed more severe depression and more impaired emotional domain of QoL in early-onset PD patients. Depression and anxiety play an important role to worsen QoL among both EOPD and TOPD patients, while no interaction was observed in the efficacy of these two psychiatric symptoms and the onset age of PD patients

Insulin-Independent and Dependent Glucose Transporters in Brain Mural Cells in CADASIL

Typical cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the human NOTCH3 gene. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy is characterized by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small vessels. Blood regulating vascular smooth muscle cells (VSMCs) appear as the key target in CADASIL but the pathogenic mechanisms remain unclear. With the hypothesis that brain glucose metabolism is disrupted in VSMCs in CADASIL, we investigated post-mortem tissues and VSMCs derived from CADASIL patients to explore gene expression and protein immunoreactivity of glucose transporters (GLUTs), particularly GLUT4 and GLUT2 using quantitative RT-PCR and immunohistochemical techniques.In vitrocell model analysis indicated that both GLUT4 and -2 gene expression levels were down-regulated in VSMCs derived from CADASIL patients, compared to controls.In vitrostudies further indicated that the down regulation of GLUT4 coincided with impaired glucose uptake in VSMCs, which could be partially rescued by insulin treatment. Our observations on reduction in GLUTs in VSMCs are consistent with previous findings of decreased cerebral blood flow and glucose uptake in CADASIL patients. That impaired ability of glucose uptake is rescued by insulin is also consistent with previously reported lower proliferation rates of VSMCs derived from CADASIL subjects. Overall, these observations are consistent with the development of severe cerebral arteriopathy in CADASIL, in which VSMCs are replaced by widespread fibrosis

Disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE) in Iran and its neighboring countries, 1990–2015

BACKGROUND: Summary measures of health are essential in making estimates of health status that are comparable across time and place. They can be used for assessing the performance of health systems, informing effective policy making, and monitoring the progress of nations toward achievement of sustainable development goals. The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) provides disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) as main summary measures of health. We assessed the trends of health status in Iran and 15 neighboring countries using these summary measures. METHODS: We used the results of GBD 2015 to present the levels and trends of DALYs, life expectancy (LE), and HALE in Iran and its 15 neighboring countries from 1990 to 2015. For each country, we assessed the ratio of observed levels of DALYs and HALE to those expected based on socio-demographic index (SDI), an indicator composed of measures of total fertility rate, income per capita, and average years of schooling. RESULTS: All-age numbers of DALYs reached over 19 million years in Iran in 2015. The all-age number of DALYs has remained stable during the past two decades in Iran, despite the decreasing trends in all-age and age-standardized rates. The all-cause DALY rates decreased from 47,200 in 1990 to 28,400 per 100,000 in 2015. The share of non-communicable diseases in DALYs increased in Iran (from 42% to 74%) and all of its neighbors between 1990 and 2015; the pattern of change is similar in almost all 16 countries. The DALY rates for NCDs and injuries in Iran were higher than global rates and the average rate in High Middle SDI countries, while those for communicable, maternal, neonatal, and nutritional disorders were much lower in Iran. Among men, cardiovascular diseases ranked first in all countries of the region except for Bahrain. Among women, they ranked first in 13 countries. Life expectancy and HALE show a consistent increase in all countries. Still, there are dissimilarities indicating a generally low LE and HALE in Afghanistan and Pakistan and high expectancy in Qatar, Kuwait, and Saudi Arabia. Iran ranked 11th in terms of LE at birth and 12th in terms of HALE at birth in 1990 which improved to 9th for both metrics in 2015. Turkey and Iran had the highest increase in LE and HALE from 1990 to 2015 while the lowest increase was observed in Armenia, Pakistan, Kuwait, Kazakhstan, Russia, and Iraq. CONCLUSIONS: The levels and trends in causes of DALYs, life expectancy, and HALE generally show similarities between the 16 countries, although differences exist. The differences observed between countries can be attributed to a myriad of determinants, including social, cultural, ethnic, religious, political, economic, and environmental factors as well as the performance of the health system. Investigating the differences between countries can inform more effective health policy and resource allocation. Concerted efforts at national and regional levels are required to tackle the emerging burden of non-communicable diseases and injuries in Iran and its neighbors